The long-term objective of this project is to determine if prevention of colorectal cancer (CRC) can be improved by developing a novel clinically relevant screen. Such a screen would identify individuals with a I1307K mutation in a cancer-susceptibility gene, and would include carefully designed surveillance and management protocols. The I1307K mutation has been identified in approximately 6 percent of Ashkenazi Jews, approximately 10 percent of Ashkenazim with CRC, and approximately 28 percent of Ashkenazim who have both CRC and a family history of CRC. Justification for allocating scarce health care resources to such a clinically relevant screen requires additional knowledge. First, although most studies to date show an increased risk for CRC in carriers of this mutation, a few do not, and the magnitude of the risk is not fully established. Second, implementation of a clinically relevant screen requires knowledge of the natural history and clinical characteristics of I1307K-associated CRC, but this too is lacking. Third, the screen will require genetic counseling, however, little known about the feasibility or psychosocial impact of genetic counseling in situations where the cancer-susceptibility mutation is of low penetrance. The current application was developed to fill these gaps in current knowledge. To learn more about risk, the study will identify 480 Ashkenazim with CRC (index cases), then the subset with mutant I1307K (expected N=48), and then the first-degree relatives of this subset with mutant I1307K (expected N=200). These data will be used to estimate cancer risk among mutation carriers using retrospective data and determine mutation-associated risk by comparing colonoscopic data between mutation carriers and their non-carrier relatives. It is hypothesized that mutation carriers will have more colonic neoplasia than noncarriers. With regard to natural history, the study will see if, in index cases, phenotypic expression of I1307K-associated CRC (age at diagnosis, frequency in each gender, histologic type, colonic location of CRC, history and pathology of other colorectal neoplasia and of extracolonic cancer, and family history of cancer) differs from CRC in non-carriers. It is hypothesized that, similar to other hereditary CRCs, CRC in mutation carriers will differ from that in noncarriers. With regard to psychosocial impact, the study will quantitatively assess the psychological impact of I1307K testing, identify predictors and moderators of distress, and inform the development of stress-reducing countermeasures. It is hypothesized that genetic testing will increase distress more in mutation carriers and test decliners than in non-carriers. Ascertaining risk, natural history and psychosocial impact will inform and may justify development of a clinically relevant screen to improve cancer prevention and decrease cancer-related mortality. Independent of screen development, this study will be the first to characterize genetic testing distress where the cancer-causing mutation is of low penetrance. Because recent advances in genomics will likely lead to the discovery of other low penetrance genes that predispose to cancer, this study could emerge as a model to aid future understanding of the interactions among modifier genes, low-penetrance mutations, the environment, and cancer.